Hyperuricemia, circulating metabolites, and the risk of cardiometabolic multimorbidity

The role of hyperuricemia in cardiometabolic multimorbidity (CMM) needs to be further confirmed. We aimed to investigate the impact of hyperuricemia on cardiometabolic multimorbidity, and to explore the metabolic mechanisms.

We conducted a prospective cohort study using data from 422,058 participants in the UK Biobank. Cardiometabolic multimorbidity was defined as having two or more cardiometabolic diseases (CMDs) identified from linked primary care, hospital, and death registry records. Cox and multistate model was used to examine the role of hyperuricemia in the progression of CMM. Elastic net regression was employed to identify metabolites associated with hyperuricemia, and a weighted hyperuricemia metabolic score was calculated to assess its association with CMM.

During a median follow-up of 13.65 years, 55,092 developed CMDs, 6484 progressed to CMM, and 2234 died with CMM. Compared with participants without hyperuricemia, those with hyperuricemia had increased risks of any CMDs (HR = 1.23, 95% CI: 1.20-1.26, P < 0.001), and CMM (HR = 1.32, 95% CI: 1.23-1.42, P < 0.001). Mendelian randomization confirmed causal effects of hyperuricemia on CMDs and CMM. Furthermore, hyperuricemia metabolic score composed of 126 differential metabolites was significantly associated with CMDs (HR = 1.24, 95% CI: 1.21-1.27) and CMM (HR = 1.36, 95% CI: 1.28-1.44). In multi-state analyses, the metabolic score was associated with higher risks of transition from health to CMD (HR = 1.25, 95% CI: 1.22-1.28) and from CMD to CMM (HR = 1.15, 95% CI: 1.07-1.22).

In this large cohort study, hyperuricemia was both observationally and genetically associated with increased risk of cardiometabolic diseases and subsequent progression to cardiometabolic multimorbidity. Hyperuricemia-related metabolic signatures may provide additional insights into the biological processes underlying cardiometabolic disease progression.